3.2 Investigations and treatment
Currently, there is no cure for osteogenesis imperfecta, but a series of treatments can be employed to alleviate symptoms and improve the quality of life. Treatment modalities include pharmacotherapy, physical therapy, and surgical intervention[10]. Pharmacotherapy involves the use of calcium supplements, vitamin D, and other nutritional supplements to increase bone density and improve skeletal health. Physical therapy includes rehabilitation exercises and orthotic devices to help patients improve posture and mobility. Surgical intervention is primarily reserved for severe spinal curvature and hip joint issues[11]. For this patient, we administered calcium supplements and vitamin D, along with some physical training, as the patient does not exhibit spinal curvature or joint deformities and does not currently require surgical intervention.
Discussion:In 1979, Sillence et al[12]. first proposed a standard classification system for OI based on the severity of clinical manifestations, ranging from Type I to Type IV. The classifications are as follows[13]: Type I is associated with mild clinical features, including blue sclera and no apparent dentinogenesis imperfecta, and typically does not result in disability; Type II is the most severe, characterized by blue sclera, a small chest, rib fractures, pulmonary infections, and often leads to perinatal death due to respiratory failure; Type III, the most severe survivable type of OI, typically presents with progressive bodily deformities such as severe short stature and significant spinal curvature, without blue sclera; and Type IV is a moderate form of the disease characterized by normal sclera and incomplete dentinogenesis, with patients exhibiting more severe clinical features than Type I OI but milder than Type III. In the present case, the patient’s stature was slightly smaller than that of a normal newborn, and radiographic examination at 5 months old revealed slender long bones in the limbs and underdeveloped hip joints. There were no obvious deformities of the spine or limbs, and the patient did not have blue sclera. Based on the clinical presentation, the patient was diagnosed with Type IV OI. Osteogenic Imperfecta is primarily caused by abnormalities in the quantity or structure of Type I collagen. Type I collagen is the primary component
of the extracellular matrix of bone cells, is the most common type of collagen in the body, and is found predominantly in tissues such as the bone, cornea, dermis, and tendons. Therefore, its quantity and quality are closely related to bone strength[14-15]. COL1A1 is located at 17q21.33, comprising 52 exons. Mutations in this gene can decrease the quantity or instability of Type I collagen, resulting in increased bone fragility.
In this case report, through genetic sequencing, we identified a heterozygous variant in the coding region of the COL1A1 gene (Chr17:48263290): NM__000088.4:c.4097T>A (p.Ile1366Asn) . This variant was highly correlated with the clinical phenotype of the patient, with a REVEL predicted score of 0.878, and was classified as a likely pathogenic variant according to ACMG classification[16]. Subsequently, the mutation site was verified using Sanger sequencing. The COL1A1 c.4097T>A variant occurs at position 4097 in the coding region of COL1A1, where thymine is replaced by adenine, resulting in the substitution of isoleucine with asparagine at position 1366 of the encoded protein. Owing to this amino acid substitution, the structure of Type I collagen is abnormal,ultimately leading to OI. COL1A1 gene mutations that cause abnormalities in Type I collagen structure most commonly involve the substitution of glycine with other amino acids. Glycine plays a crucial role in the triple helical structure of collagen, and its substitution disrupts this structure[17]. In the present case, genetic testing revealed an amino acid substitution of isoleucine with asparagine, which was classified as a missense mutation. This mutation has not been recorded in the GnomAD, ExAC, or Thousand Genomes Project databases. Furthermore, we found that the patient’s parents did not harbor this mutation (Table 1), indicating that this variant was likely a de novo mutation, although the possibility of parental germ cell mosaicism cannot be ruled out. In conclusion, OI is a rare genetic disorder, and genetic testing is crucial for its diagnosis, in addition to analysis of symptoms and auxiliary examinations. Overall, analysis of the present case revealed a rare variant (COL1A1 exon c.4097T>A) that we believe is linked to Type IV OI in the Chinese population. Overall, the results of the present study contribute to the current knowledge regarding the spectrum of pathogenic COL1A1 gene mutations in a Chinese population with OI.References:
1. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet.
2004;363(9418):1377-1385 .
2. Orioli IM, Castilla EE, Barbosa-Neto JG, et al. Birth prevalence rate of skeletal dysplasia.J Med Genet. 1986;23:328–32 .
3. Stevenson DA, Carey JC, Byrne JL, Srisukhumbowornchai S, Feldkamp ML. Analysis of skeletal dysplasia in a Utah population.AmJ Med GenetA. 2012; 158A:1046–54 .
Kuurila K, Kaitila I, Johansson R, Grénman R. Hearing loss in Finnish adults with osteogenesis imperfecta: a nationwide survey.AnnOtol RhinolLaryngol. 2002;111:939–46 .
Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment Am J Med Genet A. 2014;164A(6):1470-1481. [published correction appears in Am J Med GenetA. 2015 May;167A(5):1178] .
6. Makareeva E, Sun G, Mirigian LS, et al. Substitutions for arginine at position 780 in triple helical domain of the α1(I) chain alter folding of the type I procollagen molecule and cause osteogenesis imperfecta. PLoS One. 2018;13(7):e0200264 .
7.Li L, Mao B, Li S, et al. Genotypic and phenotypic characterization of Chinese patients with osteogenesis imperfecta. Hum Mutat. 2019;40(5):588-600 .
  1. Deguchi M, Tsuji S, Katsura D, Kasahara K, Kimura F, Murakami T. Current Overview of Osteogenesis Imperfecta. Medicina (Kaunas) . 2021;57(5):464. Published 2021 May 10.
  2. Valera Ribera C, Martinez-Ferrer À, Flores Fernández E, et al. Snyder-Robinson syndrome: differential diagnosis of osteogenesis imperfecta. Osteoporos Int . 2022;33(5):1177-1180.
  3. Rossi V, Lee B, Marom R. Osteogenesis imperfecta: advancements in genetics and treatment. Curr Opin Pediatr . 2019;31(6):708-715.
  4. Hidalgo Perea S, Green DW. Osteogenesis imperfecta: treatment and surgical management. Curr Opin Pediatr . 2021;33(1):74-78.
12.Sillence DO, Senn A, Danks DM. Genetic heterogeneity in
osteogenesis imperfecta.J Med Genet. 1979;16:101–16 .
13.Marini JC, Forlino A, Bächinger HP, Bishop NJ, Byers PH, Paepe A, et al. Osteogenesis imperfecta. Nat Rev Dis Primers.2017;3:17052 .
14. Eyre DR, Weis MA. Bone collagen: new clues to its mineralization mechanism from recessive osteogenesis imperfecta.CalcifTissue Int. 2013;93:338–47 .
15.Gug C, Caba L, Mozos I, et al. Rare splicing mutation in COL1A1 gene identified by whole exomes sequencing in a patient with osteogenesis imperfecta type I followed by prenatal diagnosis: A case report and review of the literature. Gene. 2020;741:144565.
16.Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
17. Peng H, Zhang Y, Long Z, et al. A novel splicing mutation in COL1A1 gene caused type I osteogenesis imperfecta in a Chinese family. Gene. 2012;502(2):168-171 .
Table 1. Results of genetic testing (SNVs, Indels)
Gene Chromosomal position HGVS nominate Gene subregion Variant type Zygotic state ACMGgrade
(hg19) Proband Father Mother
COLIA I chr17: NM-000088.4: Exon50 Missensevariatio Heterozygosis Wildtype Wild type May cause
48263290 c.4097T>A diseas
p.Ile1366A sn